Prostate cancers are generally tumors with low proliferative indices that depend on androgens for growth. Following castration these tumors regress, but later there is progression to an androgen-independent phenotype that is ultimately lethal for the patient. Members of the Her-kinase axis have been demonstrated to be overexpressed in human prostate cancer (significantly more in the androgen independent state) and the axis has been implicates to be involved with the emergence of the androgen independent phenotype. The overall goals of this project are to use the androgen dependent and independent xenograft models of prostate cancer to determine the role of the various members of the Her-kinase axis in the development of androgen independence in prostate cancer cells. The methods and schedule to target Her-kinase directed therapy as well as appropriate surrogate molecular endpoints for response in prostate cancer will be evaluated. We hypothesize that members of the Her-kinase axis are necessary for the development of androgen independence by the tumors and that we can effectively delay the emergence of androgen independence of prostate cancer with Her-kinase-directed therapy. This will be tested in the xenograft models of prostate cancer with the intention that, if successful, the evaluation will be translated into human clinical trials, first, to validate the molecular surrogates for response and then, to demonstrate the prevention of the emergence of androgen independence by blocking Her-kinase axis signaling.